Ocular hypotensive agents

ABSTRACT

The present invention relates to ocular hypotensive agents which contains 13,14-dihydro-15-keto-prostagandins, which shows no transient ocular hypertensive response that PGs usually show.

This is a continuation of Application No. 07/246,059 filed Sept. 19,1988 now U.S. Pat. No. 5,601,153.

BACKGROUND OF THE INVENTION

The present invention relates to ocular hypotensive agents whichcontains 13,14-dihydro-15-keto-prostaglandins.

Prostaglandins (hereinafter referred to as PGs) is the name given to thegroup of fatty acids which show various physiological activities andcontained in human and animal tissues and organs. PGs essentiallycontain the prostanoic acid skeleton of the following formula: ##STR1##and some synthetic products may contain the above skeleton with somemodification.

PGs are classified into several types according to their five-memberedring, for example, ##STR2## and the like. Further, they are classifiedinto PG₁ s containing 5,6-single bond: ##STR3## PG₂ s containing5,6-double bond: ##STR4## and PG₃ s containing 5,6-and 17,18-doublebonds: ##STR5##

PGs are known to have various pharmacological and physiologicalactivities, for example, vasodilation, induction of inflammation,platelet aggregation, contraction of uterine muscle, enteron contractionand the like. However, PGs also possesses various other activities,therefore there are some problems to use them as medicines. That is,when PGs are administered to obtain a single pharmaceutical activity,they often exhibit other activities is side effects. Accordingly, theinvestigations of PGs as a medicine have aimed to enhance the emergencyof the main pharmaceutical activity. However, these investigations havebeen insufficient.

Among PGs, for example, PGAs, PGDs, PGEs, PGFs are known to possessocular hypotensive potency.

For example, there is described in Japanese Patent Application KOKAI No.1418/1984 claiming a priority based on U.S. Ser. No. 374165(1982) byLaszlo Z. Bite that PGF₂ has a high ocular hypotensive activity, and15-keto-PGF₂ α has also it though a very little; and further in JapanesePatent Application KOKAI No. 66122/1988 claiming priorities based onthree U.S. Ser. Nos. 839056 (1986), 892387(1986) and 022046 (1987) thatPGA, PGB and PGC can be used for a treatment of glaucoma.

However, when topical application of these PGs, topically to rabbiteyes, they are accompanied with transient ocular hypertensive response,and still pronounced conjunctival and iridal hyperemia, and further sideeffects such as lacrimation, eye mucus, lid closure and the like areobserved. Accordingly, there are some problems when PGs are used asremedies for glaucoma or ocular hypotensive agents.

On the other hand, PGs wherein the carbon atoms at the 13-14 positionsare saturated and the carbon atom at the 15 position forms a carbonylgroup are found to exist in human or animal metabolites. These13,14-dihydro-15-keto-prostaglandins (hereinafter referred to as13,14-dihydro-15-keto-PGs) are known to be naturally producedmetabolites by enzymatic metabolism of the corresponding PGs in vivo.These 13,14-dihydro-15-keto-PGs have been reported to hardly exhibitvarious physiological activities that PGs possess and bepharmacologically and physiologically inactive metabolites (see, ActaPhysiologica Scandinavica, 66, p.509-(1966)) .

SUMMARY OF THE INVENTION

It has been found the above metabolites cause intraocular pressurereduction without any transient ocular hypertensive response that PGsusually show. Further, among 13,14-dihydro-15-keto-PGs, or carboxylicacid, salts, esters, compounds having a 2,3-double bond, or a 5,6-triplebond, or compounds having substituents at any of C-3, C-6, C-16, C-17,C-19 and/or C-20 positions, compounds having a lower alkyl orhydroxyalkyl group at the C-9 and/or C-11 position instead of thehydroxyl group, possess enhanced ocular hypotensive potency, and these13,14-dihydro-15-keto-PGs may exhibit ocular hypotensive effect withouttransient ocular hypertensive response, and with absolutely no orextremely reduced side effects such as hyperemia. Further, we have found° hat these 13,14-dihydro-15-keto-PGs are accompanied with no orextremely reduced peculiar central and peripheral physiologicalactivities which are simultaneously caused by PGs, and further they haveno effects on enteron, trachea or bronchus which are characteristic ofPGs.

BRIEF DESCRIPTION OF THE DRAWINGS Brief Description of Drawings:

FIG. 1 is a graph showing change in intraocular pressure with time afterapplication of prostaglandins E₂ to rabbits, wherein applied drugs wereas follows:

(1) 13,14-dihydro-15-keto-PGE₂

(2) PGE₂

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides ocular hypotensive agents containing13,14-dihydro-15-keto-PGs as active ingredients.

In the present invention, 13,14-dihydro-15-keto-PGs means PGs whereincarbons at the 13-14 positions are saturated and carbon at the 15position forms a carbonyl group.

In this description, 13,14-dihydro-15-keto-PGs are expressed as follows.That is, in 13,14-dihydro-15-keto-PGs, the carbons constituting theα-chain, ω-chain and 5-membered ring are numbered according to the basicskeleton as follows: ##STR6## That is, in the basic skeleton, theconstituent carbon atoms are numbered in such a way that the carbon atomin carboxylic acid is C-1, and the α-chain contains C-2 - C-7, thenumber increasing toward the ring, the five-membered ring contains C-8 -C-12, and the -chain contains C-13 - C-20. When the carbons of theα-chain are fewer, the numbers of the carbons ensuing C-2 should beproperly shifted, and when more than 7, the compound is named providedthat the carbon at the 2 position has a substituent instead of thecarboxyl group (at C-1 position). When the ω-chain contains fewer carbonatoms, they should be numbered correspondingly smaller than 20, and whenmore than 8, the carbon atoms at the 21 position and thereafter shouldbe regarded as a substituent. As configuration, it is consideredaccording to that of the above essential skeleton unless otherwisedescribed.

For example, PGD, PGE and PGF mean compounds having a hydroxyl group atthe C-9 and/or C-11 positions. In the present intention, PGs includethose having other group instead of the hydroxyl group on the C-9 and/orC-11 positions, they being named as 9-dehydroxy-9-substituted or11-dehydroxy-11-substituted compounds.

13,14-Dihydro-15-keto-pGs us®d in th®present invention may be PGswherein the carbon atoms at the 13-14 positions are saturated and thecarbon atom at the 15 position forms a carbonyl group, and13,14-dihydro-15-keto-PG₁ s containing a 5,6-single bond,13,14-dihydro-15-keto-PG₂ s containing a 5,6-double bond,13,14-dihydro-15-keto-PG₃ s containing both 5,6- and 17,18-double bondsmay be used.

The typical examples of the 13,14-dihydro-15-keto-PGs used in thepresent invention are shown below:

13,14-dihydro-15-keto-PGA₁ s, 13,14-dihydro-15-keto-PGA₂ s,

13,14-dihydro-15-keto-PGA₃ s, 13,14-dihydro-15-keto-PGB₁ s,

13,14-dihydro-15-keto-PGB₂ s, 13,14-dihydro-15-keto-PGB₃ s,

13,14-dihydro-15-keto-PGC₁ s, 13,14-dihydro-15-keto-PGC₂ s,

13,14-dihydro-15-keto-PGC₃ s, 13,14-dihydro-15-keto-PGD₁ s,

13,14-dihydro-15-keto-PGD₂ s, 13,14-dihydro-15-keto-PGD₃ s,

13,14-dihydro-15-keto-PGE₁ s, 13,14-dihydro-15-keto-PGE₂ s,

13,14-dihydro-15-keto-PGE₃ s, 13,14-dihydro-15-keto-PGF₁ s,

13,14-dihydro-15-keto-PGF₂ s, 13,14-dihydro-15-keto-PGF₃ s,

13,14-dihydro-15-keto-PGJ₁ s, 13,14-dihydro-15-keto-PGJ₂ s,

13,14-dihydro-15-keto-PGJ3s or the like.

These 13,14-dihydro-15-keto-PGs show strong ocular hypotensive potencywithout showing transient ocular hypertensive response as well as sideeffects such as pronounced conjunctival or iridal hyperemia,lacrimation, lid closure and the like, or extremely reduced, if any.Accordingly, these 13,14-dihydro-15-keto-PGs are extremely effective asocular hypotensive agents. Further, depending on such ocular hypotensiveeffect, they may be used for glaucoma therapy.

In the present invention, the ocular hypotensive effect of13,14-dihydro-15-keto-PGs may be especially remarkable in prostaglandinsof the general formula: ##STR7## wherein, A is ##STR8## (in which R ishydroxyl, hydroxyalkyl or alkyl); Y is a saturated or unsaturated C2-6hydrocarbon chain (some of the carbon atoms constituting the hydrocarbonchain may form a carbonyl group, and the hydrocarbon chain may besubstituted with one or more atoms or groups); Z is a C₁₋₁₀ saturated orunsaturated hydrocarbon forming a straight-chain, branched-chain or ring(the hydrocarbon may be substitued with atoms or groups)]orphysiologically acceptable salts derived from the general formula [I]orthose having an esterified carboxyl group.

A saturated or unsaturated C₂₋₆ hydrocarbon chain Y includes a srraighthydrocarbon chain such as an alkyl, alkenyl, alkynyl and the like.Especially, a hydrocarbon chain with 6 carbons is preferred.

The examples of an unsaturated hydrocarbon chain Y include, for example,PGs wherein carbons at 2-3 positions or 5-6 positions are unsaturatedlybonded.

Some of the carbons forming the hydrocarbon chain Y may form a carbonylgroup. The typical example includes 6-keto-PG₁ s wherein the carbon atthe 6 position constituting a carbonyl group.

The hydrocarbon chain Y may be substituted with one or more atoms orgroups. Such atoms or groups include, for example, a halogen atom suchas a fluorine, chlorine or bromine atom; an alkyl group such as methyl,ethyl; a hydroxyl group. The typical example is PGs having one or morealkyl groups at the carbon at the 3 position.

Z means a C₁₋₁₀ saturated or unsaturated hydrocarbon group. Thehydrocarbon itself may form a ring or may be substituted with one ormore atoms or groups.

As the hydrocarbon group Z, those with a C₃₋₉ straight chain areparticularly preferred. Those with five carbons corresponds to thegeneral PGs with an ω-chain having eight carbons. Accordingly, asdescribed above, the hydrocarbon Z having more than 6 carbons areassumed to be a substituent of the carbon at the 20 position in theω-chain (i.e., a hydrocarbon having seven carbons may be referred to as20-ethyl-PGs).

The unsaturated bond may be at any position in Z. However, Z without anunsaturated bond is preferred. The examples of the hydrocarbon Z forminga ring include a cyclo-pentyl or cyclohexyl group wherein carbons at 16or 17 position in the ω-chain may be constituent of the ring.

The hydrocarbon Z may be substituted with one or more atoms or groups.Such atoms or groups include a halogen atom such as a fluorine, chlorineor bromine atom; an alkyl group such as a methyl, ethyl, isopropyl orisopropenyl group; an alkoxy group such as a methoxy or ethoxy group; ahydroxyl group; a phenyl group; a phenoxy group and the like. Theposition of the substituent atom(s) or group(s) may not be limited, buttypically, they may be at 16, 17, 19 and/or 20 position in the ω-chain.Particularly, compounds having one or two same or different atoms at theC-16 position, for example, a halogen atom such as a fluorine atom or asubstituent, for example, an alkyl group such as a methyl, ethyl,hydroxyl phenyl which may contain one or more substituents, benzyl,phenoxy, or cycloalkyl group such as a cyclopentyl or cyclohexyl groupwhich contains the C-16 position as a constituent; an alkyl group suchas methyl at the C-17 or C-19 position: an alkyl group such as a methyl,ethyl, isopropyl, isopropenyl or alkoxy group such as a methoxy, ethoxyor propoxy group at the C-20 position are preferred.

PGs may include the compounds PGD, PGE, PGF which contain a hydroxylgroup at the C-9 and/or C-11 position. In the present invention, PGsfurther include the compounds having a hydroxyalkyl or alkyl groupinstead of the hydroxyl group at the C-9 and/or C-11 position.Accordingly, the 3,14-dihydro-15-keto-PGs of the present inventioninclude the compound of the general formula [I], wherein R is ahydroxyl, hydroxyalkyl or alkyl group. Such hydroxyalkyl grouppreferably include a hydroxymethyl or 1-hydroxyethyl, 2-hydroxyethyl or1-methyl-1-hydroxyethyl group. As the alkyl group, a lower alkyl group,especially a methyl or ethyl group are preferred.

The configuration of R for the carbon at the 9 and/or 11 position may bean α, β or mixture thereof.

PGs of the present invention may be salts or those with an esterifiedcarboxyl group. Such salts include physiologically acceptable salts, forexample, those of an alkali metal such as sodium, potassium; those of analkaline earth metal such as calcium, magnesium; those ofphysiologically acceptable an ammonium salt such as ammonia,methylamine, dimethylamine, cyclopentylamine, benzylamine, piperidine,monoethanolamine, diethanolamine, monomethylmonoethanolamine,tromethamine, lysine, tetralkylammonium salt and the like. Such an esterincludes, for a example, methyl, ethyl, propyl, butyl, isopropyl,t-butyl, 2-ethylhexyl, straight or branched-chain alkyl ester which maycontain an unsaturated bond; for example, ester having an alicyclicgroup such as a cyclopropyl, cyclopentyl or cyclohexyl group; an estercontaining an aromatic group such as a benzyl or phenyl group (whereinthe aromatic group may contain one or more substituents); a hydroxyalkylor alkoxyalkyl ester such as a hydroxyethyl, hydroxyisopropyl,polyhydroxyisopropyl, methoxyethyl, ethoxyethyl or methoxyisopropylgroup; an alkylsilyl ester e.g., a trimethylsilyl or triethylsilylester; a tetrahydropyranyl ester.

Preferred esters include, for example, a straight or branched loweralkyl ester such as a methyl, ethyl, propyl, n-butyl, isopropyl ort-butyl ester; or a benzyl ester; a hydroxyalkyl ester such as ahydroxyethyl or hydroxyisopropyl ester.

The carboxyl group at the C-1 position of 13,14-dihydro-15-keto-PGs ofthe present invention may be any of the above described groups. Amongthem, esters, especially the C₁₋₄ alkyl ester are preferred consideringemergency of ocular hypotensive effect.

13,14-Dihydro-15-keto-PGs of the present invention may include theisomers of the above compounds. Examples of such isomers includeketo-hemiacetal tautomers between the C₆ -carbonyl and C₉ -hydroxyl, orthe C₁₁ -hydroxyl and C₁₅ -C₆ -carbonyl; or optical isomers; geometricalisomers and the like.

Keto-hemiacetal tautomers between the C₁₁ -hydroxyl group and C₁₅-carbonyl may be readily formed especially in 13,14-dihydro-15-keto-PGEshaving electrophilic group such as a fluorine atom at the C-16 position.

The mixture of the isomers, for example, those of racemic body,tautomers of hydroxyl compound and hemiacetals may show similar effectas that shown by the respective compound.

In the present invention, especially preferred 13,14-dihydro-15-keto-PGsmay contain a 5,6-single or double bond, or a carbonyl group at the 6position carbon atom. Another preferred groups are13,14-dihydro-15-keto-PGs having 20-24 carbon atoms. Still otherpreferred groups are 13,14-dihydro-15-keto-PGs wherein the carbon atomat the 16 position may be substituted with a halogen atom or an alkylgroup, and further, 13-14-dihydro-15-keto-PGs having more than 20carbons and an alkyl group at C-19 position.

Particularly, the compounds having a C₁₋₄ alkyl, for example, a methyl,ethyl, propyl or butyl group at the C-20 position, that is, having aprolonged ω-chain show enhanced ocular hypotensive effect with littleside effects such as hyperemia. Accordingly, such compounds arepreferred.

That is, in 13,14-dihydro-15-keto-PGs used in the present invention,those having an alkyl group at the C-20 position may provideparticularly preferable result, neglecting the structure of thefive-membered ring, or the existence of double bond or othersubstituents. Particularly, those wherein the alkyl group is ethyl(wherein the ω-chain contains a C₁₀ straight chain) may show the mostpronounced ocular hypotensive effect, scarcely showing side effects suchas hyperemia, thereby providing the most preferable product as a whole.

In the present invention, PGs are named according to the prostanoic acidskeleton. If named according to IUPAC, for example, PGE₁ corresponds to7-[(lR,2R,3R)-3-hydroxy-2-[(E)-(3S)-3-hydroxy-1-octenyl]-5-oxo-cyclopentyl]-heptanoicacid; PGE₂,(Z)-7-[(1R,2R,3R)-3-hydroxy-2-[(E)-(3S)-3-hydroxy-1-octenyl]-5-oxo-cyclopentyl]-hept-5-enoicacid; 13,14-dihydro-15-keto-16R,S-fluoro-PGE₂,(Z)-7-[(1R,2S,3R)-2-[(4RS)-4-fluoro-3-oxo-1-octyl]-3-hydroxy-5-oxo-cyclopentyl]-hept-5-enoicacid; 13,14-dihydro-15-keto-20-ethyl-11-dehydroxy-11R-methyl-PGE₂ methylester, methyl7-[(lR,2S,3R)-3-methyl-2-(3-oxo-1-decyl)-5-oxo-cyclopentyl]-hept-5-enoate;13,14-dihydro-6,15-diketo-19-methyl-PGE2 ethyl ester, ethyl7-[(lR,2R,3R)-3-hydroxy-2-(7-methyl-3-oxo-1-octyl)-5-oxo-cyclopentyl]-6-oxo-heptanoate. PGF₁ α corresponds to7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(E)-(3S)-3-hydroxy-1-octenyl]-cyclopentyl]-heptanoicacid; PGF₂ α,(Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(E)-(3S)-3-hydroxy-1-octenyl]-cyclopentyl]-5-heptenoicacid; 13,14-dihydro-15-keto-20-ethyl-PGF₂ α isopropyl ester, isopropyl(Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-(3-oxo-1-decyl)-cyclopentyl]-hept-5-enoate;13,14-dihydro-15-keto-20-methyl-PGF₂ αmethyl ester, methyl(Z)-7-[(lR,2R,3R,5S)-3,5-dihydroxy-2-(3-oxo-1-nonyl)-cyclopentyl]-hept-5-enoate.Other PGs may also be named in the same way.

13,14-Dihydro-15-keto-PGs of the present invention include isomers ofthe above compounds. The example of these isomers includesketo-hemiacetal tautomers between the C-6 carbonyl and C-9 hydroxylgroups, or the C-11 hydroxyl and C-15 carbonyl groups; or opticalisomers; geometrical isomers and the like.

The keto-hemiacetal tautomers between the C-11 hydroxyl and C-15carbonyl groups may be readily formed, for example, in the case of13,14-dihydro-15-keto-PGs which contain one or more electrophilic groupssuch as a fluorine atom at the 16 position. The mixture of the isomers,for example, those of racemic body or tautomers of the hydroxy compoundwith hemiacetals may shown similar effect as that shown by a respectivecompound.

The above 13,14-dihydro-15-keto-PGs of the present invention may beprepared according to the methods described, for example, in JapanesePatent Application Nos. 63-18326, 63-18327 and 63-108329. Thesedescriptions may be included in the present invention.

In the process for preparing 13,14-dihydro-15-keto-compound:

A commercially available (-)-Corey lactone, which is used as a startingmaterial, is subjected to Collins oxidation to give an aldehyde. Thealdehyde is allowed to react with dimethyl (2-oxoalkyl)phosphonate anionto give an α,β-unsaturated ketone, and the resultant is reduced toketone. The carbonyl group of the ketone is allowed to react with a diolto give a ketal, thereby protected, then a corresponding alcohol isobtained by elimination of the phenylbenzoyl group, and the resultinghydroxy group is protected with dihydropyran to give a tetrapyranylether. Thus, precursors of PGs wherein the ω-chain is13,14-dihydro-15-keto-alkyl can be obtained.

Using the above tetrapyranyl ether as a starting material, 6-keto-PG₁ sof the formula: ##STR9## may be obtained as follows:

The tetrapyranyl ether is reduced using diisobutyl aluminium hydride andthe like to give a lactol, which is allowed to react with a ylideobtained from (4-carboxybutyl)triphenylphosphonium bromide, and theresultant is subjected to esterification followed by cyclization,combining the 5,6-double bond and the C-9 hydroxyl group with NBS oriodine, providing a halide. The resultant is subjected todehydrohalogenation with DBU and the like to give a 6-keto compound,which is subjected to Jones oxidation followed by deprotection to givethe objective compound.

Further, PG₂ s of the formula: ##STR10## may be obtained as follows:

The above tetrapyranyl ether is reduced to the lactol, which is allowedto react with a ylide obtained from (4-carboxybutyl)triphenylphosphonium bromide to give a carboxylic acid. The resultant issubjected to esterification followed by Jones oxidation and deprotectionto give the objective compound.

In order to obtain PG₁ s of the formula: ##STR11## using the abovetetrapyranyl ether as a starting material, in the same manner as PG₂ ofthe formula: ##STR12## the 5,6-double bond of the resulting compound issubjected to catalytic reduction followed by deprotection.

To prepare 5,6-dehydro-PG₂ s containing a hydrocarbon chain of theformula: ##STR13## a monoalkyl copper complex or a diaklyl coppercomplex of the formula: ##STR14## is subjected to 1,4-addition with4R-t-butyldimethylsilyloxy-2-cyclopenten-1-one, and the resulting copperenolate is seized with 6-carboalkoxy-1-iodo-2-hexyne or a derivativethereof.

PGs containing a methyl group instead of a hydroxy group at the C-11position may be obtained as follows: PGA obtained by Jones oxidation ofthe hydroxy group at the C-9 position of the 11-tosylate is allowed toreact with a dimethyl copper complex to give 11-dehydroxy-11-methyl-PGE.Alternatively, an alcohol obtained after elimination of p-phenylbenzoylgroup is converted to a tosylate. An unsaturated lactone obtained by DBUtreatment of the tosylate is converted to a lactol. After introductionof an α-chain using Wittig reaction, the resulting alcohol (C-9position) is oxidized to give PGA. PGA is allowed to react with dimethylcopper complex to give 11-dehydroxy-11-methyl-PGE. The resultant isreduced using sodium borohydride and the like to give11-dehydroxy-11-methyl-PGF.

PGs containing a hydroxymethyl group instead of a hydroxyl group at theC-11 position is obtained as follow: 11-dehydroxy-11-hydroxymethyl-PGEis obtained by a benzophenone-sensitized photoaddition of methanol toPGA. The resultant is, for example, reduced using sodium borohydride togive 11-dehydroxy-11-hydroxymethyl-PGF.

16-Fluoro-PGs may be obtained using dimethyl (3-fluoro-2-oxoalkyl)phosphonate anion in the preparation of an α, β-unsaturated ketone.Similarly, 19-methyl-PGs may be obtained using a dimethyl(6-methyl-2-oxoalkyl)phosphonate anion.

The preparations in the present invention are not construed to belimited to them, and suitable means for protection, oxidation, reductionand the like may be employed.

13,14-Dihydro-15-keto-PGs of the present invention can be used asremedies for animal and human, and, in general, used for systemic orlocal application by oral administration, intravenous injection,subcutaneous injection, suppository, collyrium, oculentum and the like.The dosage varies depending on animals, human, age, weight, conditions,therapeutic effect, administration route, treatment time and the like.

The solid composition for oral administration of the present inventionincludes tablets, preparations, granules and the like. In such a solidcomposition, one or more active ingredients may be mixed with at leastone inactive diluent, for example, lactose, mannitol, glucose,hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, magnesium aluminate metasilicate and the like. According tothe usual work-up, the composition may contain additives other than aninactive diluent, for example, a lubricant such as magnesium stearate;disintegrant such as fibrous calcium(gluconate; a stabilizer such asetherified cyclodextrin, for example, α,β- or γ-cyclodextrin,dimethyl-α-, dimethyl-β-, trimethyl-γ- or hydroxypropyl-8-cyclodextrin,branched cyclodextrin such as glucosyl-, maltosyl-cyclodextrin,formulated cyclodextrin, cyclodextrin containing sulfur, mitthoprotol,phospholipid and the like. When the above cyclodextrins are used, aninclusion compound with cyclodextrins may be sometimes formed to enhancestability. Alternatively, a phospholipid may be sometimes used to form aliposome, resulting in enhanced stability.

Tablets or pills may be coated with film soluble materials in thestomach or intestine such as sugar, gelatin, hydroxypropyl cellulose,hydroxypropylmethyl cellulose phthalate and the like, or with more thantwo layers. Further, they may be formed as capsules with absorbablesubstances such as gelatin.

A liquid composition for oral administration may contain apharmaceutically acceptable emulsion, solution, suspension, syrup,elixir as well as a generally used inactive diluent, for example,purified water, ethanol and the like. Such a composition may contain, inaddition to the inactive diluent, adjuvants such as wetting agents andsuspensions, sweetening agents, flavoring agents, preservatives and thelike.

Other compositions for oral administration include a spray formulated byknown method, which may contain one or more active ingredients.

Injection for parenteral administration according to the presentinvention includes a steril, agueous or nonaqueous solution, suspension,emulsion and the like.

A diluent for such an aqueous solution and suspension includes, forexample, injectable distilled water, physiological saline and Ringer'ssolution.

A diluent for non-aqueous solution and suspension includes, for example,propylene 91ycol, polyethylene 91ycol, vegetable oil such as olive oil,alcohols such as ethanol polysorbate and the like. Such a compositionmay contain adjuvants such as preservatives, wetting agents,emulsifiers, dispersants, stabilizers and the like. These aresterilized, for example, by filtration through a bacteria-holdingfilter, compounding with germicides, gas sterilization orradio-sterilization. These may be used by preparing a sterile solidcomposition and dissolving in sterile water or sterile solvent forinjection before use.

The collyrium according to the present invention may include a sterileaqueous or non-aqueous solution, suspension and the like. The diluentfor such an aqueous solution or suspension includes, for example,distilled water or a physiological saline. The diluent for thenon-aqueous solution or suspension may include an edible oil, liquidparaffin, mineral oil, propylene glycol, p-octyldodecanol and the like.Further, in order to make isotonic to tears, isotonic agents such assodium chloride, benzalkonium chloride, phedrine chloride, procainechloride, chloram phenicol, sodium citrate, or in order to maintain thepH value constant, buffer such as a borate or phosphate buffer may beused. Moreover, stabilizers such as sodium sulfite, sodium carbonate,EDTA, propylene glycol; thickening agents such as glycerin,carboxymethyl cellulose, carboxyvinyl polymer; diluents such aspolysorbate, macrogols, alminum monostearate; preservatives such asparaben, benzyl alcohol, sorbic acid; and further resolvents, vehiclesmay be compounded. These may be sterilized, for example, by thefiltration through a bacteria-holding filter or heat sterilization. Inthe preparation of collyrium, pH value and ion strength of the agent areespecially important, and they may be optionally adjusted to the optimalvalue depending on the types and amounts of other active ingredients oradditives used.

The oculentum according to the present invention may contain vaseline,selen 50, plastibase, macrogols as a base, and surfactant such aspolysorbate, Tween, purified lanolin, jelly such as carboxymethylcellulose, methylcellulose, carboxyvinyl polymer to enhancehydrophilism.

The ocular hypotensive agent of the present invention may be used as aremedy for glaucoma utilizing its ocular hypotensive potency. When usedas the remedie for treatment of glaucoma, the present agents may becompounded with the conventional cholinergic ocular hypotensive agent(e.g., pilocarpine, carbachol, which possesses excellent mioticactivity) anticholinesterases (e.g., demecarium, D.F.P., echothiophate),physostigmine salicylate, pilocarpine hydrochloride as miotics,mannitol, glycerin, isosorbide as hyperosmotic agent for intravenousinjection, chlorobutanol, benzalkonium chloride, propylparabene,methylparaben, ethylparaben, butylparaben as preservatives forcollyrium, penicillin, sulfonamide, chloramphenicol, cortisone,chlorpheniramine for prevention and treatment of other inflammation.

The present invention will be illustrated in the following examples.

PREPARATIONS

Preparations of 13,14-dihydro-15-keto-20-ethyl-PGA₂ isopropyl ester,13,14-dihydro-15-keto-20-ethyl-PGE₂ isopropyl ester and13,14-dihydro-15-keto-20-ethyl-PGF₂ α isopropyl ester (cf. Preparationchart I):

1) Preparation of1S-2-oxa-3-oxo-6R-(3-oxo-1-trans-decenyl)-7R-(4-phenylbenzoyloxy}-cis-bicyclo[3.3.0]-octane(3):

Commercially available (-)-Corey lactone (1) (7 g) was subjected toCollins oxidation in dichloromethane to give aldehyde (2). The resultantwas allowed to react with dimethyl (2-oxononyl)phosphonate (4.97 g anionto give 1S-2-oxa-3-oxo-6R-(3,3-ethylendioxy-1-trans-decenyl)-7R-(4-phenylbenzoyloxy)-cis-bicyclo[3.3.0]-octane(3).

2) Preparation oflS-2-oxa-3-oxo-6R-(3-oxodecyl)-7R-(4-phenylbenzoyloxy)-cis-bicyc-1o[3.3.0]-octane(4):

Unsaturated ketone (3) (7.80 g]was reduced in ethyl acetate (170 ml)using 5% Pd/C under hydrogen atmosphere. The product obtained after theusual work-up (4) was used in the following reaction.

3) Preparation oflS-2-oxa-3-oxo-6R-(3,3-ethylenedioxy-decyl)-7R-(4-phenylbenzoyloxy)-cis-bicyclo[3.3.0]-octane(5):

Saturated ketone (4) was converted to ketal (5) in dry benzene (150 ml)using ethylene glycol and p-toluenesulfonic acid (catalytic amount).

4) Preparation of1S-2-oxa-3-oxo-6R-(3,3-ethylenedioxy-decyl)-7R-hydroxy-cis-bicyclo[3.3.0]-octane(6):

To a solution of ketal (5) in absolute methanol (150 ml) was addedpotassium carbonate (2.73 g). The mixture was stirred overnight at roomtemperature. After neutralization with acetic acid, the resultant wasconcentrated under reduced pressure. The resulting crude product wasextracted with ethyl acetate. The organic layer was washed with a diluteaqueous solution of sodium bicarbonate and a saline, and dried. Thecrude product obtained after evaporation was chromatographed to givealcohol (6). Yield; 3.31 g

5) Preparation of lactol (7):

Alcohol (6) (0.80 g) was reduced in dry toluene (8 ml) using DIBAL-H at-78 ° C to give lactol (7).

6) Preparation of 13,14-dihydro-15,15-ethylenedioxy-20-ethyl-PGF₂ α (8):

A DMSO solution of lactol (7) was added to ylide prepared from(4-carboxybutyl)triphenylphosphonium bromide (3.65 g). The reactionmixture was stirred overnight to give carboxylic acid (8).

7) Preparation of 13,14-dihydro-15,15-ethylenedioxy-20-ethyl-PGF₂ αisopropyl ester (9):

Carboxylic acid (8) was converted to13,14-dihydro-15,15-ethylenedioxy-20-ethyl-PGF₂ α isopropyl ester (9)using DBU and isopropyl iodide in acetonitrile.

Yield; 0.71 g .

8) Preparation of 13,14-dihydro-15-keto-20-ethyl-isopropyl ester (10):

13,14-Dihydro-15,15-ethylenedioxy-20-ethyl-PGF₂ α isopropyl ester (9)(0.71 g) was kept in acetic acid/THF/water (3/1/1) at 40 ° C. for 3hours. The crude product obtained after concentration under reducedpressure was chromatographed to give 13,14-dihydro-15-keto-20-ethyl-PGF₂α isopropyl ester (10).

Yield; 0.554 g .

9) Preparation of 13,14-dihydro-15-keto-20-ethyl-PGA₂ isopropyl ester(12):

A solution of 13,14-dihydro-15-keto-20-ethyl-PGF₂ α isopropyl ester (10)(0.125 g) and p-toluenesulfonyl chloride (0.112 g) in pyridine (5 ml)was maintained at 0 ° C. for 2 days. According to the usual work-up,tosylate (11) was obtained.

Tosylate (11) was subjected to Jones oxidation in acetone (8 ml) at -25° C. The crude product obtained after the usual work-up waschromatographed to give 13,14-dihydro-15-keto-20-ethyl-PGA₂ α isopropylester (2).

Yield; 0.060 g.

10) Preparation of13,14-dihydro-15,15-ethylenedioxy-20-ethyl-11-t-butyldimethylsiloxy-PGF.sub.2α isopropyl ester (13):

13,14-Dihydro-15,15-ethylenedioxy-20-ethyl-PGF₂ α isopropyl ester (9)(3.051 g) was dissolved in dry N,N-dimethylformamide (25 ml),t-butyldimethylsilyl chloride (1.088 g) and imidazole (0.49 g) was addedthereto. The resultant was stirred at room temperature overnight. Thereaction mixture was concentrated under reduced pressure, and theresulting crude product was chromatographed to give13,14-dihydro-15,15-ethylenedioxy-20-ethyl-11-t-butyldimethylsiloxy-PGF.sub.2α isopropyl ester (13).

Yield; 2.641 g .

11) Preparation of13,14-dihydro-15,15-ethylenedioxy-20-ethyl-11-t-butyldimethylsiloxy-PGE.sub.2isopropyl ester (14):

13,14-Dihydro-15,15-ethylenedioxy-20-ethyl-11-t-butyldimethylsiloxy-PGF.sub.2α isopropyl ester (13) (1.257 g) was subjected to Jones oxidation at -40° C. After the usual work-up, the resulting crude product waschromatographed to give13,14-dihydro-15,15-ethylenedioxy-20-ethyl-11-t-butyldimethylsiloxy-PGE.sub.2isopropyl ester (14).

Yield; 1.082 g .

12) Preparation of 13,14-dihydro-15-keto-20-ethyl-PGE₂ isopropyl ester(15):

To a solution of13,14-dihydro-15,15-ethylene-dioxy-20-ethyl-11-t-butyldimethylsiloxy-PGE.sub.2isopropyl ester (14) in acetonitrile was added hydrofluoric acid (46%aqueous solution). The mixture was stirred at room temperature for 40minutes The crude products obtained after usual work-up waschromatographed to give 13,14-dihydro-15-keto-20-ethyl-PGE₂ isopropylester (15).

Yield; 0.063 g (97 %) . ##STR15##

EXAMPLE 1

For the purpose of tonometry, Japanese White male rabbits (2.5-3.0 Kg)were fixed on braces, and after topical anesthetization with 0.4%oxybuprocaine hydrochloride, intraocular pressure was measured using apheumatic applanation tonometer (manufactured by Japan Alcon K.K.).

The test drugs were suspended in a physiological saline. A 50 μl aliquotof 50 μl of the suspension (25 μg/eye of the test drug) was topicallyapplied to one eye. The contralateral control eye received physiologicalsaline. Intraocular pressure was measured at every 1 hr, until 6 hr,after topical application. In this experiment, 6 rabbits per group wereused, and the mean values of intraocular pressure of the treated eye ateach time were calculated. The results are shown in FIG. 1.

Test drugs:

(1) 13,14-dihydro-15-keto-PGD2; ()

(2) PGE₂ ; ()

As is obvious from the results, 13,14-dihydro-15-keto-PGs including13,14-dihydro-15-keto-PGE₂ and the like are proved to possess ocularhypotensive potency without transient ocular hypertensive response thatPGs including PGE₂ possess.

EXAMPLE 2

For the purpose of tonometry, Japanese White male rabbits (2.5-3.0 Kg)were fixed on braces. After topical anesthetization with 0.4%oxybuprocaine hydrochloride, intraocular pressure was measured using apheumatic applanation tonometer (manufactured by Japan Alcon). After thetopical application of 50 μl of the suspensions of the test drugs in aphysiological saline to one eye, the intraocular pressure was measuredand the intraocular pressure reduction (%) caused by each test drug wascalculated. At the same time, the extend of conjunctival hyperemia wasobserved. The results are shown in Table 1.

                  TABLE 1 (1)                                                     ______________________________________                                                  Dose       Percent change                                           Test Drug (μg/eye)                                                                              of IOP      Hyperemia                                    ______________________________________                                        (1)       100        22          +                                            (2)       100        26          +                                            (3)       100        24          +                                            (4)       100        30          +                                            (5)       100        31          -                                            (6)       100        33          -                                            (7)        50        23          -                                            (8)        50        27          -                                            (9)       100        40          ++                                           ______________________________________                                         * The extent of conjunctival hyperemia:                                       - scarcely observed                                                           ± extremely weak hyperemia                                                 + slight hyperemia                                                            ++ pronounced hyperemia                                                       +++ severe hyperemia                                                          Test drugs:                                                                   (1) 13,14dihydro-15-keto-PGA.sub.1 methyl ester                               (2) 13,14dihydro-15-keto-PGA.sub.1 isopropyl ester                            (3) 13,14dihydro-15-keto-PGA.sub.2 ethyl ester                                (4) 13,14dihydro-15-keto-PGA.sub.2 isopropyl ester                            (5) 13,14dihydro-15-keto-20-ethyl-PGA.sub.1 methyl ester                      (6) 13,14dihydro-15-keto-20-ethyl-PGA.sub.1 isopropyl ester                   (7) 13,14dihydro-15-keto-20-ethyl-PGA.sub.2 methyl ester                      (8) 13,14dihydro-15-keto-20-ethyl-PGA.sub.2 isopropyl ester                   (9) PGA.sub.2                                                            

                  TABLE 1 (2)                                                     ______________________________________                                                  Dose       Percent change                                           Test Drug (μg/eye)                                                                              of IOP      Hyperemia                                    ______________________________________                                        (10)      250         7          +                                            (11)      250        10          +                                            (12)      250        15          +                                            (13)      250        20          +                                            (14)      250        21          -                                            (15)      250        23          -                                            (16)      100        18          -                                            (17)      100        20          -                                            (18)      250        25          ++                                           ______________________________________                                         Test drugs:                                                                   (10) 13,14dihydro-15-keto-PGB.sub.1 methyl ester                              (11) 13,14dihydro-15-keto-PGB.sub.2 isopropyl ester                           (12) 13,14dihydro-15-keto-PGB.sub.2 methyl ester                              (13) 13,14dihydro-15-keto-PGB.sub.2 isopropyl ester                           (14) 13,14dihydro-15-keto-20-ethyl-PGB.sub.1 methyl ester                     (15) 13,14dihydro-15-keto-20-ethyl-PGB.sub.1 isopropyl ester                  (16) 13,14dihydro-15-keto-20-ethyl-PGB.sub.2 methyl ester                     (17) 13,14dihydro-15-keto-20-ethyl-PGB.sub.2 isopropyl ester                  18) PGB.sub.2                                                            

                  TABLE 1 (3)                                                     ______________________________________                                                  Dose       Percent change                                           Test Drug (μg/eye)                                                                              of IOP      Hyperemia                                    ______________________________________                                        (19)      250         8          +                                            (20)      250        11          +                                            (21)      250        18          +                                            (22)      250        20          +                                            (23)      250        20          -                                            (24       250        22          -                                            (25       100        21          -                                            (26)      100        25          -                                            (27)      250        23          ++                                           ______________________________________                                         Test drugs:                                                                   (19) 13,14dihydro-15-keto-PGC.sub.1 methyl ester                              (20) 13,14dihydro-15-keto-PGC.sub.1 isopropyl ester                           (21) 13,14dihydro-15-keto-PGC.sub.2 methyl ester                              (22) 13,14dihydro-15-keto-PGC.sub.2 isopropyl ester                           (23) 13,14dihydro-15-keto-20-ethyl-PGC.sub.1 methyl ester                     (24) 13,14dihydro-15-keto-20-ethyl-PGC.sub.1 isopropyl ester                  (25) 13,14dihydro-15-keto-20-ethyl-PGC.sub.2 methyl ester                     (26) 13,14dihydro-15-keto-20-ethyl-PGC.sub.2 isopropyl ester                  (27) PGC.sub.2                                                           

                  TABLE 1 (4)                                                     ______________________________________                                                  Dose       Percent change                                           Test Drug (μg/eye)                                                                              of IOP      Hyperemia                                    ______________________________________                                        (28)      250        15          ±                                         (29)      250        17          ±                                         (30)      250        20          ±                                         (31)      250        18          ±                                         (32)      250        21          ±                                         (33)      250        25          ±                                         (34)      250        23          ±                                         (35)      100        13          +                                            (36)      250        28          ±                                         (37)      250        30          ±                                         (38)      250        24          ±                                         (39)      250        28          ±                                         (40)      250        31          ±                                         (41)      100        18          -                                            (42)      100        20          -                                            (43)      100        25          -                                            (44)      100        23          -                                            (45)      100        20          -                                            (46)      250        28          +++                                          ______________________________________                                         Test drugs:                                                                   (28) 13,14dihydro-15-keto-PGD.sub.1 methyl ester                              (29) 13,14dihydro-15-keto-PGD.sub.1 ethyl ester                               (30) 13,14dihydro-15-keto-PGD.sub.2 ethyl ester                               (31) 13,14dihydro-15-keto-PGD.sub.2 nbutyl ester                              (32) 13,14dihydro-15-keto-5,6-dehydro-PGD.sub.2 methyl ester                  (33) 13,14dihydro-15-keto-5,6-dehydro-9PGD.sub.2                              (34) 13,14dihydro-15-keto-5,6-dehydro-9PGD.sub.2 methyl ester                 (35) 13,14dihydro-15-keto-16R,S-fluoro-PGD.sub.2 methyl ester                 (36) 13,14dihydro-15-keto-16,16-dimethyl-PGD.sub.2 methyl ester               (37) 13,14dihydro-15-keto-19-methyl-PGD.sub.2 methyl ester                    (38) 13,14dihydro-15-keto-20-methoxy-PGD.sub.2                                 (39) 13,14dihydro-15-keto-20-methoxy-PGD.sub.2 nbutyl ester                  (40) 13,14dihydro-15-keto-16R,S-methyl-20-methoxy-PGD.sub.2 methyl ester      (41) 13,14dihydro-15-keto-20-ethyl-PGD.sub.1 methyl ester                     (42) 13,14dihydro-15-keto-20-ethyl-PGD.sub.1 ethyl ester                      (43) 13,14dihydro-15-keto-20-ethyl-PGD.sub.2 methyl ester                     (44) 13,14dihydro-15-keto-20-ethyl-PGD.sub.2 ethyl ester                      (45) 13,14dihydro-15-keto-20-methoxyethyl-PGD.sub.2 methyl ester              (46) PGD.sub.2                                                           

                  TABLE 1 (5)                                                     ______________________________________                                                  Dose       Percent change                                           Test Drug (μg/eye)                                                                              of IOP      Hyperemia                                    ______________________________________                                        (47)      50         30          +                                            (48)      10         20          +                                            (49)      10         18          +                                            (50)      10         23          +                                            (51)      25         25          ±                                         (52)      25         32          +                                            (53)      25         18          +                                            (54)      25         20          +                                            (55)      25         23          ±                                         (56)      25         16          +                                            (57)      10         32          +                                            (58)      10         30          +                                            (59)      10         31          +                                            (60)       5         26          +                                            (61)      10         18          +                                            (62)      10         21          +                                            (63)      10         25          +                                            (64)      25         21          ±                                         (65)      25         19          ±                                         (66)      25         23          ±                                         (67)      25         20          -                                            (68)      25         25          -                                            (69)      10         30          -                                            (70)      10         31          -                                            (71)      10         24          -                                            (72)      10         12          -                                            (73)      10         32          +++ *                                        ______________________________________                                         *Lid closure and lacrimation were observed.                                   Test drugs:                                                                   (47) 13,14dihydro-15-keto-PGE.sub.1 ethyl ester                               (48) 13,14dihydro-6,15-diketo-PGE.sub.1 ethyl ester                           (49) 13,14dihydro-6,15-diketo-PGE.sub.1 nbutyl ester                          (50) ±13,14dihydro-6,15-diketo-PGE.sub. 1 ethyl ester                      (51) 13,14dihydro-6,15-diketo-11-dehydroxy-11R-methyl-PGE.sub.1 ethyl         ester                                                                         (52)                                                                          13,14dihydro-6,15-diketo-16R,S-fluoro-11-dehydroxy-11R-methyl-PGE.sub.1       ethyl ester                                                                   (53) 13,14dihydro-6,15-diketo-16,16-dimethyl-PGE.sub.1 ethyl ester            (54) 13,14dihydro-6,15-diketo-19-methyl-PGE.sub.1 methyl ester                (55) 13,14dihydro-6,15-diketo-11-dehydroxy-11R-hydroxymethyl-PGE.sub.1        methyl ester                                                                  (56) 13,14dihydro-15-keto-PGE.sub.2                                           (57) 13,14dihydro-15-keto-PGE.sub.2 methyl ester                              (58) 13,14dihydro-15-keto-PGE.sub.2 isopropyl ester                           (59) 13,14dihydro-15-keto-Δ.sup.2PGE.sub.2 methyl ester                 (60) 13,14dihydro-15-keto-16R,S-fluoro-PGE.sub.2 ethyl ester                  (61) 13,14dihydro-15-keto-3,16-dimethyl-PGE.sub.2 methyl ester                (62) 13,14dihydro-15-keto-16R,S-hydroxy-PGE.sub.2 ethyl ester                 (63) 13,14dihydro-15-keto-19-methyl-PGE.sub.2 ethyl ester                     (64) 13,14dihydro-15-keto-20-methoxy-PGE.sub.2 methyl ester                   (65) 13,14dihydro-15-keto-20-methoxy-Δ.sup.2PGE.sub.2 methyl ester      (66) 13,14dihydro-15-keto-16-dimethyl-20-methoxy-PGE.sub.2 methyl ester       (67) 13,14dihydro-15-keto-20-ethyl-PGE.sub.1 methyl ester                     (68) 13,14dihydro-6,15-diketo-20-methyl-PGE.sub.1 ethyl ester                 (69) 13,14dihydro-15-keto-20-ethyl-PGE.sub.2 methyl ester                     (70) 13,14dihydro-15-keto-20-ethyl-PGE.sub.2 ethyl ester                      (71) 13,14dihydro-15-keto-20-n-propyl-PGE.sub.2 methyl ester                  (72) 13,14dihydro-15-keto-20-ethyl-11-dehydroxy-11R-methyl-PGE.sub.2          methyl ester                                                                  (73) PGE.sub.2                                                           

                  TABLE 1 (6)                                                     ______________________________________                                                  Dose       Percent change                                           Test Drug (μg/eye)                                                                              of IOP      Hyperemia                                    ______________________________________                                        (74)      100        28          +                                            (75)      100        22          +                                            (76)      100        33          +                                            (77)      100        38          +                                            (78)       20        25          +                                            (79)       10        42          ±                                         (80)      100        41          +                                            (81)      250        21          +                                            (82)      250        40          +                                            (83)      100        33          ±                                         (84)       25        17          -                                            (85)       50        28          -                                            (86)       50        28          -                                            (87)       50        25          -                                            (88)       50        23          -                                            (89       250        23          +                                            (90)      250        25          ±                                         (91)      250        26          -                                            (92)       25        43          ±                                         (93)       10        26          ±                                         (94)      250        30          -                                            (95)      250        18          -                                            (96)      100        46          +++*                                         (97)       25        27          +++*                                         (98)       25        31          +++*                                         ______________________________________                                         * Lid closure and lacrimation were observed.                                  Test drugs:                                                                   (74) 13,14dihydro-15-keto-PGF.sub.1 α ethyl ester                       (75) 13,14dihydro-15-keto-PGF.sub.2 α methyl ester                      (76) 13,14dihydro-15-keto-PGF.sub.2 α  ethyl ester                      (77) 13,14dihydro-15-keto-9β,11PGF.sub.2 methyl ester                    (78) 13,14dihydro-15-keto-16R,S-fluoro-PGF.sub.2                              (79) 13,14dihydro-15-keto-16R,S-fluoro-PGF.sub.2 α methyl ester         (80) 13,14dihydro-15-keto-16,S-fluoro-11-dehydroxy-11R-methyl-PGF.sub.2       α methyl ester                                                          (81) 13,14dihydro-15-keto-16,16-dimethyl-PGF.sub.2 α ethyl ester        (82) 13,14dihydro-15-keto-17S-methyl-PGF.sub.2 α ethyl ester            (83) 13,14dihydro-15-keto-20-ethyl-PGF.sub.1 α methyl ester             (84) 13,14dihydro-15-keto-20-ethyl PGF.sub.2                                  (85) 13,14dihydro-15-keto-20-ethyl PGF.sub.2 α methyl ester             (86) 13,14dihydro-15-keto-20-ethyl PGF.sub.2 α ethyl ester              (87) 13,14dihydro-15-keto-20-ethyl PGF.sub.2 α isopropyl ester          (88) 13,14dihydro-15-keto-20-ethyl PGF.sub.2 α nbutyl ester             (89) 13,14dihydro-15-keto-20-methyl PGF.sub.2 α methyl ester    Tes     drugs: (90) 13,14-dihydro-15-keto-20-n-propyl-PGF.sub.2 α methyl     ester (91) 13,14-dihydro-15-keto-20-n-butyl-PGF.sub.2 α methyl ester     (92) 13,14-dihydro-15-keto-20-ethyl-16R,S-fluoro-PGF.sub.2 α (93)     13,14-dihydro-15-keto-20-ethyl-16R,S-fluoro-PGF.sub.2 α methyl ester     (94) 13,14-dihydro-15-keto-20-ethyl-11-dehydroxy-llR-methyl-

PGF₂ α methyl ester (95)13,14-dihydro-15-keto-20-ethyl-16R,S-fluoro-11-dehydroxy-11R-methyl-PGF.sub.2α methyl ester (96) PGF₂ α (97) PGF₂ α methyl ester (98) PGF₂ αisopropyl ester

The n.m.r. of the above compounds used in the Example 2 and Mass areshown hereinafter:

'H n.m.r. was determined using heavy chloroform as a solvent by a NMRspectrometer R-90H available from Hitachi Seisakusho.

Mass was determined by a mass spectrometer M-80B available from HitachiSeisaku-sho;

EI method: at ionization patential of 70 eV, SIMS method: silverplate-glycerin matrix.

Compound (3)

δ: 0.88(3H, t, J=6Hz), 1.25(3H, t, J=7Hz), 1.10 14 2.75(22H, m),4.11(2H, q, J=7Hz), 5.37(2H, m), 6.12(lH, dd, J=6Hz, J=2.5Hz), 7.53(lH,dd, J=6Hz, J=3Hz)°

Compound (8)

δ: 0.86(3H, t, J=5.5Hz), 1.21(6H, d, J=6Hz), 1.05-2.75(26H, m), 4.96(lH,hept, J=6Hz), 5.37(2H, m), 6.09(lH, dd, J=6Hz, J=2Hz, 7.50(lH, J=6Hz,J=2.5Hz)

Mass(EI) m/z 404(M⁺), 345(M+- i- C₃ H₇₀)

Compound (30)

δ: 0.89(3H, t, J=6Hz), 1.26(3H, t, J=7Hz), 1.06 - 2.93(25H, m), 4.13(2H,q, J=7Hz), 4.41(lH, m), 5.47(2H, m)

Compound (34)

δ: 0.98(3H,t, J=6Hz), 1.09-2.96(25H, m), 3.63(3H, s), 4.19(lH, m).

Compound (35)

δ: 0.91(3H, t, J=6Hz), 1.1-2.93(23H, m), 3.64(3H, s), 4.3-4.5(1.5H, m),4.98(0.5H, dd, J=6Hz), 5.50(2H, m)

Mass(SIMS) m/z 385(M+H)+, 367(M++1-H₂₀), 365(M⁺ +1-HF).

Compound(37)

δ: 0.86(6H, d, J=7Hz), 0.94-2.90(24H, m), 3.64(3H, s),

4.38(lH, m), 5.43(2H, m) .

Mass(EI) m/z 380(M ), 362(M+-H₂₀), 331, 234, 222 .

Compound(40)

δ: 1.05(3H, d, J=7Hz), 0 80-2.83(24H, m), 3.28(3H, s), 3.32(2H, t,J=6Hz), 3.64(3H, s), 4.29-4.47(lH, m), 5.44(2H, m) .

Compound(45)

δ: 1.10-2.95(29H, m), 3.30(3H, s), 3.33(2H, t, J=6Hz), 3.66(3H, s),4.38(lH, m), 5.44(2H, m)

Compound(55)

δ: 8-2.98(26H, m), 2.71(lH, m),

δ: 0.86(6H, d, J=6Hz), 0.98-2.98(26H, m), 2.71(lH, m), 3.63(3H, s),3.50-3.81(2H, m) .

Mass(EI) m/z 410(M⁺), 392(M⁺ -18), 379, 361 ,

Compound(58)

δ: 0.88(3H, t, J=6Hz), 1.22(6H, d, J=6.5Hz), 1.07-3.03(25H, m), 4.03(lH,m), 4.97(lH, hept, J=6.5Hz), 5.37(2H, m) .

Compound(67)

δ: 0.87(3H, t, J=6Hz), 1.03-2.84(33H, m), 3.64(3H, s), 3.98(lH, m) .

Compound(68)

δ: 0.87(3H, t, J=6Hz), 1.23(3H, t, J=7Hz), 1.03-2.88(29H, m), 4.08(2H,q, J=7Hz), 3.86-4.23 (lH m) .

Compound(69)

δ: 0.88(3H, t, J=6Hz), 1.07-2.90(29H, m), 3.64(3H, s), 4.02(lH, m),5.35(2H, m) .

Compound(70)

δ: 0.87(3H, t, J=6Hz), 1.23(3H, t, J=7Hz), 1.07-2.83(29H, m), 4.08(2H,q, J=7Hz), 3.79-4.22(lH, m), 5.34(2H, m), Mass(EI) m/z 408,390,345 .

Compound(71)

δ: 0.87(3H, t, J=5Hz), 1.00-2.83(31H, m), 3.63(3H, s), 3.86-4.15(lH, m),5.34(2H, m) .

Mass(SIMS) m/z 409,391,369 .

Compound(72)

δ: 0.87(3H, t, J=5Hz}, 1.11(3H, d, J=6Hz), 1.00-2.60(29H, m), 3.63(3H,s), 5.33(2H, m) . Mass(EI) m/z 392,374,361,343.

Compound(83)

δ: 0.87(3H, t, J=6Hz), 1.15-2.70(34H, m), 3.63(3H, s), 3.86(lH, m),4.15(lH, m) .

Mass(EI) m/z 398(M⁺),380(M⁺ -18),362,349 .

Compound(84)

δ: 0.86(3H, t, J=6Hz), 1.15-2.70(28H, m), 3.85(lH, m), 4.12(lH, m),5.10-5.75(5H, m) .

Mass(EI) m/z 364(M+-18), 346 .

Compound(85)

δ: 0.87(3H, t, J=6Hz), 1.10-2.65(30H, m), 3.63(3H, s), 3.85(lH, m),4.13(lH, m), 5.38(2H, m) .

Mass(SIMS) m/z 397(M⁺ +1), 379(M⁺ +1-H₂ O ), 361(M⁺ +1-2H₂ O), 345,330 .

Compound(86)

δ: 0.87(3H, t, J=6Hz), 1.24(3H, t, J=7Hz), 1.10-2.95(30H, m), 3.85(lH,m), 4.08(2H, q, J=7Hz), 3.93-4.25(lH, m), 5.38(2H, m) .

Mass(EI) m/z 410(M⁺),392(M+-18),374 .

Compound(87)

δ: 0.87(3H, t, J=6Hz), 1.22(6H, d, J=6.5Hz), 1.10-2.75(30H, m), 3.85(lH,m), 4.13(lH, m), 4.95(lH, hept, J=6.5Hz), 5.38(2H, m) .

Mass(EI) m/z 424(M⁺),406(M⁺ -18),388,347 o

Compound(88)

δ: 0.70-1.03(6H, m), 1.10-3.05(34H, m), 3.84(lH, m), 4.03(2H, t,J=6.5Hz), 4.10(lH, m), 5.38(2H, m) ,

Mass(EI) m/z 420(M⁺),402(M⁺ -18),376,347 ;

Compound(89)

δ: 0.87(3H, t, J=6Hz), 1.15-2.70(28H, m), 3.62(3H, s), 3.83(lH, m),4.12(lH, m), 5.37(2H, m).

Mass(SIMS) m/z 383(M⁺ +1), 365(M⁺ +1-18), 347 .

Compound (90)

δ: 0.87(3H, t, J=6Hz), 1.10-2.70(32H, m), 3.63(3H, s), 3.85(lH, m),4.12(lH, m), 5.38(2H, m) .

Compound(91)

δ: 0.87(3H, t, J=6Hz), 1.10-2.70(34H, m), 3.63(3H, s), 3.83(lH, m),4.12(lH, m), 5.38(2H, m) .

Compound(92)

δ: 0.87(3H, t, J=6Hz), 1.10-2.90 (26H, m), 3.87(lH, m), 4.12(lH, m),4.43(0.5H, m), 4.50-5.10(3H, brs),4.99(0.5H, m), 5.38(2H, m).

Mass(EI) m/z 400(M⁺), 382(M⁺), 382(M⁺ -18),362,344 .

Compound(94)

δ: 0.87(3H, t, J=5.5Hz), 1.06(3H, d, J=6Hz), 1.15-2.55(30H, m), 3.63(3H,s), 4.08(1H, m), 5.38(2H, m).

Mass(EI) m/z 394(M+), 375(M+-18), 358,344 .

Compound(95)

δ: 0.88(3H, t, J=6Hz), 1.08(3H, d, J=6Hz), 1.15-2.75(28H, m), 3.63(3H,s), 4.09(lH, m), 4.42(0.5H, m), 4.97(0.5H, m), 5.38(2H, m) .

Mass(EI) m/z 412(m⁺), 394(M⁺ -18) .

EXAMPLE 3

For the purpose of tonometry, Japanes White male rabbits (2.5 Kg -3.0Kg) were fixed on braces. After anesthetization by topical applicationof 0.4 % oxybuprocaine hydrochloride, the intraocular pressure wasdetermined using a pheumatic applanation tonometer (manufactured byJapan Alcon K.K.).

The test drugs were suspended in a physiological saline, and a 50 μlaliquot (25 μg/eye of the test drug) was topically applied to one eye,while the other eye received physiological saline. At every 0.5 hr aftertopical application, up to 2 hr, the intraocular pressure was measuredand side effects were observed and assessed. In this experiment, 6rabbits per group were used, and mean value of the intraocular pressureof the treated eye (the change (mmHg) provided that the intraocularpressure at 0 hr is 0) and rating of the assessment of the side effectsat each time were determined. The side effects were rated according tothe following standard.

The results are shown in Tables 2 and 3.

                  TABLE 2                                                         ______________________________________                                        (Charge in intraocular pressure; Means ± S.E. mmHg)                        Time (hr)                                                                     Test Drug                                                                             0.5       1.0        1.5     2.0                                      ______________________________________                                        1       -1.7 ± 0.5                                                                           -3.5 ± 1.0                                                                            -2.5 ± 1.4                                                                         -1.2 ± 1.8                            4       +4.0 ± 1.1                                                                           +0.8 ± 1.4                                                                            +0 5 ± 1.0                                                                         -0.5 ± 1.9                            2       -2.9 ± 0.7                                                                           -5.4 ± 1.5                                                                            -6.4 ± 1.1                                                                         -6.3 ± 1.1                            5       +5.3 ± 0.8                                                                           +10.3 ± 0.4                                                                           +5.4 ± 1.4                                                                         +0.2 ± 1.4                            3       -2.3 ± 1.0                                                                           -4.3 ± 1.9                                                                            -4.8 ± 1.1                                                                         -4.8 ± 0.7                            6       +2.2 ± 1.1                                                                           +3.8 ± 2.5                                                                            +1.5 ± 1.9                                                                         -1.0 ± 1.8                            ______________________________________                                    

                  TABLE 3                                                         ______________________________________                                        (Evaluation of side effects)                                                         Time (hr)                                                              Test Drug                                                                              0.5       1.0       1.5     2.0                                      ______________________________________                                        1        2.2 ± 0.2                                                                            2.0 ± 0.3                                                                            1.5 ± 0.2                                                                          1.2 ± 0.4                             4        3.2 ± 0.4                                                                            3.0 ± 0 6                                                                            2.8 ± 0.5                                                                          2.5 ± 0.3                             2        2.8 ± 0.3                                                                            3.1 ± 0.3                                                                            2.7 ± 0.4                                                                          2.2 ± 0.5                             5        5.0 ± 0.0                                                                            5.2 0.2   5.0 ± 0.0                                                                          4.8 ± 0.2                             3        2.0 ± 0.4                                                                            2.3 ± 0.6                                                                            2.0 ± 0.5                                                                          1.7 ± 0.7                             6        5.0 ± 0.0                                                                            5.2 ± 0.2                                                                            5.3 ± 0.2                                                                          5.3 ± 0.3                             ______________________________________                                         Standard of the evaluation of the side effects (ocular response)         

    ______________________________________                                        Scale for Scoring Ocular Lesions                                              ______________________________________                                        1) Cornea                                                                     A) Opacity-degree of density (area most dense                                 taken for reading)                                                            No Opacity                 0                                                  Scattered or diffuse area, details of iris                                                               1                                                  clearly visible                                                               Easily discernible translucent areas,                                                                    2                                                  details of iris slightly obscured                                             Opalescent areas, no details of iris                                                                     3                                                  visible, size of pupil barely                                                 discernible                                                                   Opaque, iris invisible     4                                                  B) Area of cornea involved                                                    One quarter (or less) but not zero                                                                       1                                                  Greater than one quarter, but less                                                                       2                                                  than half                                                                     Greater than half, but less than                                                                         3                                                  three quarters                                                                Greater than three quarters, up to                                                                       4                                                  whole area                                                                    A × B × 5                                                                          Total maximum = 80                                           2) Iris                                                                       A) Values                                                                     Normal                     0                                                  Folds above normal, congestion, swelling,                                                                1                                                  circumcorneal injection (any or all of                                        these or combination of any thereof)                                          iris still reacting to light (sluggish                                        reaction is positive)                                                         No reaction to light, hemorrhage, gross                                                                  2                                                  destruction (any or all of these)                                             A × 5      Total maximum = 10                                           3) Conjunctivae                                                               A) Redness (refers to palpebral and bulbar                                    conjunctivae excluding cornea and iris)                                       Vessels normal             0                                                  Vessels definitely injected above normal                                                                 1                                                  More diffuse, deeper crimson red, individual                                                             2                                                  vessels not easily discernible                                                Diffus beefy red           3                                                  B) Chemosis                                                                   No swelling                0                                                  Any swelling above normal (includes                                                                      1                                                  nictitating membrane)                                                         Obvious swelling with partial eversion                                                                   2                                                  of lids                                                                       Swelling with lids about half closed                                                                     3                                                  Swelling with lids about half closed                                                                     4                                                  to completely closed                                                          C) Discharge                                                                  No discharge               0                                                  Any amount different from normal                                                                         1                                                  (dose not include small amounts observed                                      in inner canthus of normal animals)                                           Discharge with moistening of the lids                                                                    2                                                  and hairs just adjacent to lids                                               Discharge with moistening of the lids                                                                    3                                                  and hairs, and considerable area                                              around the eye                                                                Score (A' + B + C) × 2                                                                   Total maximum = 20                                           ______________________________________                                         Test Drugs :                                                                  1 13,14dihydro-15-keto-20-ethyl-PGF.sub.2                                     2 13,14dihydro-15-keto-20-ethyl-PGF.sub.2 α methyl ester                3 13,14dihydro-15-keto-20-ethyl-PGF.sub.2 α isopropyl ester             4 PGF.sub.2                                                                   5 PGF.sub.2 α methyl ester                                              6 PGF.sub.2 α isopropyl ester                                      

As is obvious from above results, 13,14-dihydro-15-keto-20-alkyl-PGsincluding 13,14-dihydro-15-keto-20-ethyl-PGF₂ s cause intraocularpressure reduction without transient ocular hypertensive responseconnected with PGs including PGF₂ s. Esters are proved to have astronger tendency to cause intraocular pressure reduction than carboxylacid type. Compared with PGs including PGF₂ s,13,14-dihydro-15-keto-20-alkyl-PGs including13,14-dihydro-15-keto-20-ethyl-PGF₂ s are accompanied with extremelyreduced side effects, which are hardly detectable.

EXAMPLE 4

For the purpose of tonometry, Japanese White male rabbits (2.5 Kg -3.0Kg) were fixed on braces. After anesthetization by topical applicationof 0.4 % oxybuprocaine hydrochloride, the intraocular pressure wasdetermined using on a pheumatic applanation tonometer (manufactured byJapan Alcon K.K.).

The test drugs were suspended in a physiological saline, and a 50 μlaliquot (25 μg/eye of the test drug) was topically applied to one eye,while the other eye received physiological saline. At every 1 hr aftertopical application, up to 4 hr, the intraocular pressure was Theresults are shown in Table 4 .

                                      TABLE 4                                     __________________________________________________________________________    Test Time                                                                     Drug 0      1      2      3      4                                            __________________________________________________________________________    1    21.3 ± 3.6.sup.1)                                                                 29.3 ± 3.5                                                                        22.0 ± 3.4                                                                        19.8 ± 1.5                                                                        18.5 ± 1.9                                            (+37.6).sup.2)                                                                        (+3.3)                                                                               (-7.0)                                                                              (-13.1)                                      2    17.7 ± 1.5.sup.                                                                   14.3 ± 1.5                                                                        12.7 ± 3.2                                                                        12.3 ± 2.9                                                                        14.3 ± 3.8                                            (-19.2).sup.                                                                         (-28.2)                                                                              (-30.5)                                                                              (-19.2)                                      __________________________________________________________________________     Test Drugs:                                                                   1 PGE.sub.2                                                                   2 13,14dihydro-15-keto-20-ethyl-PGE.sub.2 isopropyl ester                     .sup.1) Mean ± S.E. of intraocular pressure (mmHg)                         .sup.2) Percent change of intraocular pressure (%)                       

We claim:
 1. A topical ocular composition comprising an amount effectiveas an ocular hypotensive agent of a 13,14-dihydro-15- keto prostaglandinrepresented by the formula (I): ##STR16## wherein each R isindependently hydroxy, hydroxy C₁₋₃ alkyl or C₁₋₂ alkyl; Y is asaturated or unsaturated C₂₋₆ hydrocarbon chain which is unsubstitutedor substituted by oxo, halogen, an alkyl group or hydroxyl; Z is a C₁₋₁₀saturated or unsaturated hydrocarbon forming a straight-chain, abranched-chain or a ring, which is unsubstituted or substituted byhalogen, an alkyl group, an alkoxy group, hydroxyl, a phenyl group or aphenoxy group; or the physiologically acceptable slats and carboxylicacid esters, said ester being a straight or branched-chain alkylcontaining up to one unsaturated bond, cycloakly, benzyl, phenyl,hydroxyalkyl, alkoxyalkyl, alkylsilyl or tetrahydropyranyl ester, of thecompounds of formula (I); and a pharamaceutically acceptable carrier. 2.The ocular hypotensive composition according to claim 1, wherein thecarboxyl group at the end of the α-chain in the13,14-dihydro-15-keto-prostaglanlin is in the form of an alkyl ester. 3.The ocular hypothensive composition according to claim 1, wherein the13,14-dihydro-15-prostaglandin are in the form of 20-alkyl having analkyl group at the C-20 position.
 4. The ocular hypotensive compositionof any of claims 2, 3 or 1 wherein the 13,14-dihydro-15-prostaglandin ispresent in an amount effective for treating glaucoma.
 5. The ocularhypotensive composition of any of claims 2, 3 or 1 in the form of atopical eye drop.
 6. A method for treating ocular hypertension in ahuman patient needing such treating which comprises administering tosaid patient an amount of 13,14-dihydro-15-keto-prostaglandinrepresented by the formula (I) effective to treat ocular hypertension##STR17## wherein each R is independently hydroxy, hydroxy C₁₋₃ alkyl orC₁₋₂ alkyl; Y is a saturated or unsaturated C₂₋₆ hydrocarbon chain whichis unsubstituted or substituted by oxo, halogen, an alkyl group orhydroxyl; Z is a C₁₋₁₀ saturated or unsaturated hydrocarbon forming astraight-chain, a branched-chain or a ring, which is unsubstituted orsubstituted by halogen, an alkyl group, an alkoxy group, hydroxyl, aphenyl group or a phenoxy group; or the physiologically acceptable saltsand carboxylic acid esters, said ester being a straight orbranched-chain alkyl containing up to one unsaturate bond, cycloalkyl,benzyl, phenyl, hydroxyalkyl, alkoxyalkyl, alkylsilyl ortetrahydropyranyl ester, of the compounds of formula (I).
 7. A methodfor treating glaucoma in a human patient needing such treatment whichcomprises administering to said patient an amount of13,14-dihydro-15-keto-prostaglandin represented by the formula (I)effective to treat glaucoma ##STR18## wherein each R is independentlyhydroxy, hydroxy C₁₋₃ alkyl or C₁₋₂ alkyl; Y is a saturated orunsaturated C₂₋₆ hydrocarbon chain which is unsubstituted or substitutedby oxo, halogen, an alkyl group or hydroxyl; Z is a C₁₋₁₀ saturated orunsatured hydrocarbon forming a straight-chain, a branched-chain or aring, which is unsubstituted or substituted by halogen, an alkyl group,an alkoxy group, hydroxyl, a phenyl group or a phenoxy group; or thephysiologically acceptable salts and carboxylic acid esters, said esterbeing a straight or branched-chain alkyl containing up to oneunsaturated bond, cycloalkyl, benzyl, phenyl, hydroxyalkyl, alkoxyalkyl,alkylsilyl or tetrahydropyranyl ester, of the compounds of formula (I).8. The method of claim 6, wherein the carboxyl group at the end of theα-chain in the 13,14-dihydro-15-keto-prostaglandin is in the form of analkyl ester.
 9. The method of claim 6, wherein the13,14-dihydro-15-keto-prostaglandin is in the form of 20-alkyl having analkyl group at the C-20 position.
 10. The method of claim 6, wherein the13,14-dihydro-15-keto-prostaglandin is13,14-dihydro-15-keto-20-ethyl-PGE₂ α isopropyl ester.
 11. The method ofany of claim 6 or 9, wherein said administration is topically to theeye.
 12. The method of claim 7, wherein the carboxyl group at the end ofthe α-chain in the 13,14-dihydro-15-keto-prostaglandin is in the form ofan alkyl ester.
 13. The method of claim 7, wherein the13,14-dihydro-15-keto-prostaglandin is in the form of 20-alkyl having analkyl group at the C-20 position.
 14. The method of claim 7, wherein the13,14-dihydro-15-keto-prostaglandin is13,14-dihydro-15-keto-20-ethyl-PGE₂α isopropyl ester.
 15. The method ofany of claims 7, 13 or 14 wherein said administration is topically tothe eye.